Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phophodiesterase type 5 (PDE5), commercially developed by Pfizer, Inc. as VIAGRA®. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methlypiperazine citrate, having a molecular weight of 666.7, and the following chemical structure:

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/ml in water. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing the inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5, which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
The synthesis of pyrazolopyrimidinone compounds was described as the reaction of a chlorosulfonyl compound with a cyclic amine. As the reaction progresses, however, mineral acids are produced which may further react with the product or starting materials thereby reducing the overall yield. For example, U.S. Pat. No. 5,250,534 to Bell et al. generically describes the synthesis of various pyrazolopyrimidinone compounds. A sulfonyl chloride is allowed to react with an excess of cyclic amine at room temperature to yield the desired product. The process, however, uses an excess of the cyclic amine, which can be economically prohibitive depending on the cyclic amine used. Additionally, because the protonated amine compound is similar to the final product, purification is complicated by the difficulty in removing the side-product from the reaction mixture.
The invention is directed to processes for synthesizing sildenafil citrate which reduce the undesired side-products commonly associated with known methods in the art. The present also provides soluble or easily dissolved sildenafil citrate water adduct for use in pharmaceutical compositions.